Vitamin k-active compositions



VIT K-ACTIVE COMPOSITIGNS Erhard Fernh0lz, Princeton, and Stefan Ansbacher, Highland Park, N. J., assignors to E. R. Squibb & Sons, New York, N. Y.,- a corporation of New York No Drawing. Application-July. 29, 1939,

. Serial No. 287,256

e Claims. (Cl, 167-81) This invention relates to, and has for its object the provision of, medicinal agents for hemorrhagic conditions, particularly those associated with lowered prothrombin level.

It is known that a deficiency of the accessory food factor vitamin K results in diminution of the prothrombin content or activity of the blood and consequently increases the clotting time of the blood and facilitates development of hemorrhagic conditions. Vitamin K has been concentrated and isolated irom natural sources such as alfalfa, and clinical administration has amply demonstrated its efdcacy in raising the prothrombin level of the blood and hence its value for the treatment of hemorrhagic conditions such as those frequently arising in obstructive jaundice.

We have found that a group of chemical compounds (many of which are known) is highly emcacious in raising the prothrombin level of the blood and hence are valuable substitutes tor vitamin K. This group consists of Z-methyl-Ltnaphthoquinone, Z-methyl-1,4-naphthohydroquinone {Z-methyl-I,i-naphthalenedioll, and esters of the latter. which compounds, notably Z-methyl-1,4-naphthoquinone and Z-methyl-L- naphthohydroquinone diacetate, are many times more active in raising the prothrombin level than vitamin K1, the more active vitamin-K compound; and the hydroqulnone esters enjoy the especial advantage of Ming administrable parenteraily.

The compounds may be orally administered as such (i. e., in crystalline form) or in a suitable vehicle or carrier,-as tablets, capsules, or the like. For example, being tat-soluble, they are conveniently administrable in a fatty-oil medium, inter alia, olive oil, peanut oil, sesame oil, and iatty oils containing fat-soluble vitamins-especially such as coact with the compounds-e. g, cod-liver oil and halibut-liver oil; and the hydroquinone esters may be parenterally administered, for example by intramuscular injection of a solution thereof in a fatty oil, e. g., peanut 011. Thus,

fatty-oil solutions containing 1 mg. of one of these compounds per cc., and 0.25 cc. capsules each containing 1 mg. of one of these compounds, have been successfully used for the treatment of hemorrhagic conditions resulting from lowered prothrombin level.

The esters of Z-methyl-1,4-naphthohydroquinone utiiizable in the practice of this invention include, inter alia, the monoand di-aliphatic acid (especially the lower fatty-acid) esters such as the monoacetate, the diacetate, the clipropionets, and the dibutyrate, and the monoand ill di-aromatic acid esters such as the dibenzoate. The preparation of 2-methyl-L4-naphthoquinone, 2-methyl-1,4-naphthohydroquinone, and the diacetate of the latter is described by R. J. Anderson and M. S. Newman, J. 13101., Chem, 103, 405 (1933); and other esters may of course be prepared in the same manner as the diacetate, using the desired-acid reactants, or by mono or di-esterification of Z-methyl-1,4-naphthohydroquinone in the conventional manner.

The high potency of this group of compounds in raising the prothrombin level is indicated by the fact that to bring about normal clotting of the blood of a, vitamin-K-deficient chick within six hours, the oral administration of 2 micrograms of vitamin K1 (derived from alfalfa) in 0.1 cc. of cod-liver oil is required; whereas the same result may be obtained by the administration of, for example, 0.5 microgram of 2-methyl-L4- naphthoquinone, likewise in 0.1 cc. cod-liver oil.

The efilcacy of this group of compounds as medicinal (i. e., therapeutic and/or prophylactic) agents for hemorrhagic conditions associated with loweredprothrombin level has been demon.

strated by clinical work. Thus, the oral administration of 1-4 mg. of one of these compounds in a fatty-oil (2-methyl-1,4-naphthoquinone in corn oil) brought about a normal prothrombin level of the blood within 24 hours in cases of obstructive jaundice; the oral administration of 1-4 mg. of one of these compounds in a fatty oil to-expectant mothers within a few hours before delivery brought about a greatly elevated prothrombin level in the newborn; and the oral administration of 0.5-1 mg. of one of these compounds in a fatty oil to newborn babies raised the prothromblin level considerably within a day.

The invention may be variously otherwise em- 2. A medicinal agent for hemorrhagic conditions associated with lowered prothrombin level essentially comprising a compound of the group consisting of 2 methyl 1,4 naphthoqulnone, Z-methyl-1,4-naphthohydroquinone, and esters of the latter, in a fatty oil containing fat-soluble vitamins.

3. As a medicinal agent for hemorrhagic con- .ditions, Z-methyl-1,4-naphthoquinone in a fattyoil medium.

4. A composltlon essentially comprising 2- OTHER REFERENCES methyl-1,4-naphthoqulnone in an oily medium.

m vofrgs gizlaafirggggchemische qeaellschafll. STEFAN ANSBACHER.

5 Journal 0! Biological Chemistry, vol. 108 (1938) REFERENCES CITED Page Chemical Abstracts, vol. 24, pages 858, 359 The following references are of record In the (1930). file of this patent: Journal of the American Chemical Society, vol.

v 61, July 1989. Articles on D8898 1923 to 1932. UNITED STATES PATENTS 10 A 1 Number Name Date 1,984,511 Anderson et al Dec. 18, 1984 

